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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 5  |  Issue : 1  |  Page : 14-27

Acral melanosis


Department of Dermatology and Venereology, Government Medical College and Hospital, Chandigarh, India

Date of Web Publication29-May-2018

Correspondence Address:
Shimona Garg
Department of Dermatology and Venereology, Government Medical College and Hospital, Sector 32 B, Chandigarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/Pigmentinternational.Pigmentinternational_

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  Abstract 


The term “acral” means the distal portions of the limbs (hand, foot) and the head (ears, nose). The term acral melanosis is loosely applied to an increase in melanin pigmentation, in a diffuse, reticulate, or focal pattern over the distal parts of the arms and legs. There are various causes of acral pigmentation varying from genetic to acquired, benign to malignant, autoimmune to infectious, drug-induced, nutritional deficiencies, postinflammatory, and even exogenous reasons. The pigmentation may be occurring in isolation or associated with various systemic features. An earlier age of the onset of pigmentation, a positive family history, and a reticulate or mottled pattern usually point to a genetic cause. The diffuse pattern of pigmentation is usually seen in racial, endocrine diseases, and nutritional deficiencies. Postinflammatory acral pigmentation may follow both infectious and autoimmune diseases and may even be drug induced. A correct diagnosis is important to decide on the management which varies from reassurance and counseling to active treatment. This review paper is an attempt to classify acral pigmentation based on its diverse etiological causes.

Keywords: Acral, classification, drug, pigmentation


How to cite this article:
Bhalla M, Garg S. Acral melanosis. Pigment Int 2018;5:14-27

How to cite this URL:
Bhalla M, Garg S. Acral melanosis. Pigment Int [serial online] 2018 [cited 2018 Jun 21];5:14-27. Available from: http://www.pigmentinternational.com/text.asp?2018/5/1/14/233458




  Introduction Top


In humans, the pigmentation of the skin is an adaptation response to ultraviolet radiation and is mainly due to the melanin content and partly due to hemoglobin and carotenoids.[1] Hyperpigmentation may be a result of the hyperplasia of melanocytes (due to increased sun exposure or idiopathic) or an increase in the production of melanosomes (due to hormones or irritant stimuli).[2] The pigmentation may be a normal physiological response or may be a marker of a benign and relatively easily treatable condition or may indicate a malignant condition such as melanoma. The term “acral” means the distal portions of the limbs (hand, foot) and the head (ears, nose). Acral pigmentation is a clinical diagnosis with a multitude of underlying causes which may be genetic or acquired. This term is loosely applied to an increase in melanin pigmentation, in a diffuse, reticulate, or focal pattern over the distal parts of the arms and legs. It encompasses the different morphological forms as well as the different underlying causes but there exists no clear etiological classification even in speciality textbooks. Some authors have attempted to clinically classify pigmentation into facial, truncal, acral, or flexural types based on the regional distribution of pigmentation. This review paper is an attempt to classify acral pigmentation based on its diverse etiological causes [Table 1] and to delineate the associated clinical presentation.
Table 1: Etiological classification of acral melanosis

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Racial pigmentation

The skin color and type is variable among races depending on the number, size, and shape of melanocytes as well as the distribution of melanosomes. The distribution of melanin varies between races and is also uneven in a given race with females usually having a lighter color than males. The pigmentation also varies depending on the body site, and some darkly pigmented areas are considered normal, such as the genital area, elbows, knees, knuckles, and even a mild degree of infraorbital and perioral pigmentation [Figure 1]. Acral pigmentation may be physiological in certain races that have darker complexions where it is not associated with any underlying disease. It is usually a diffuse pigmentation seen over the hands and feet. Associated longitudinal melanonychia may also be present. It does not require any treatment.
Figure 1: Racial pigmentation presenting with hyperpigmented knuckles and melanonychia

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  Genetic causes Top


The genetic reticulate pigmentary disorders usually have defects localized to keratin 5 and keratin 14 gene. The pigmentation may be the only feature in certain genetic disorders while in others it may be associated with underlying systemic features.

Genetic disorders with only pigmentation

Reticulate acropigmentation of Kitamura

This autosomal-dominant condition has been primarily reported from the Asian countries.[3] Its genetic loci overlap with Dowling Degos disease. This condition usually manifests in the first to second decade of life with well-defined, slightly depressed, black/brown macules over the hands and feet.[4] The epidermal ridge pattern over the palms may be interrupted by the presence of characteristic small pits.[5] The lesions gradually increase in number with age and may spread centripetally to involve the limbs, trunk, neck, and even face. Histologically, hyperpigmented lesions show epider­mal atrophy, elongation of rete ridges, and increased numbers of dihydroxyphenylalanine (DOPA)-positive melanocytes.[6] Camouflage is advised to the patient along with genetic counselling.[7]

Acropigmentation symmetrica of Dohi

This autosomal-dominant disorder has also been more commonly described in Asians, particularly the Japanese and Chinese.[8],[9] A mutation of the double-stranded ribonucleic acid (RNA)-specific adenosine deaminase gene (ADAR1 or DSRAD) located at the 1q21.1-q21.2 is believed to be pathogenic, because this enzyme is important for the post-transcriptional modification of the messenger RNA (RNA editing). The impaired RNA editing leads to the formation of hyperactive and hypoactive melanocytes which usually migrate the farthest to the hands and feet. This probably accounts for the acral distribution of the disorder.[10] The onset is during childhood with the lesions presenting as nonprogressive hypopigmented and hyperpigmented macules over the hands and feet [Figure 2].[8] Similar freckle-like lesions may be present over the proximal parts of the limbs, that is, knees and elbows and even on the face.
Figure 2: Multiple symmetrically distributed hypopigmented and hyperpigmented macules over hands and feet in a patient with acropigmentation of Dohi

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The histology of the hyperpigmented lesions shows increased basilar pigmentation while the hypopigmented lesions show decreased basilar pigmentation and occasional pigment incontinence.[11] Camouflage is the most logical approach for the management of the lesions though transplantation of thin split-thickness skin autografts for hypopigmented lesions and laser therapy for hyperpigmented macules especially on the face has been tried.[12],[13]

Acromelanosis albo-punctata

This inherited condition was first described by Siemens in 1964 which remained as the only described case in literature till 2012 when Arnold et al. described a second similar case. It is characterized by diffuse hyper­pigmentation on the dorsal aspects of the hands and flexures along with guttate hypopigmented and atrophic lesions. The lesions may also involve the palms and soles. Keratotic follicular papules, pili torti, and platonychia are the other associated features which have been described. Genetic testing has established it as a distinct entity from other disorders of mottled pigmentation.[14]

Genetic disorders with pigmentation and systemic features

Peutz–Jeghers syndrome

It is an autosomal-dominant disorder characterized by pigmented macules around the nose, mouth, palms, and soles along with hamartomatous gastrointestinal polyposis which have a high risk of malignant transformation.[15] The black/brown, round or oval, 1–5 mm diameter macules over the buccal mucosa and lips usually appear during infancy or early childhood, but may even be present at birth or develop later in life with a tendency to increase in size during adolescence.[16] Rarely, the pigmented macules affect the back of the hands and tips of the fingers and toes [[Figure 3]a and [Figure 3]b]. Intestinal manifestations include numerous polyps in the jejunum, ileum, and less frequently in the colon, rectum, stomach, and duodenum. Patients with Peutz–Jeghers syndrome (PJS) have a 10–18-fold greater lifetime cancer risk especially of gastrointestinal malignancy than the general population.[17] These patients need to be monitored for the development of malignancy while counseling and reassurance is all that is needed for the pigmented lesions.
Figure 3: (a) A child of Peutz–Jeghers syndrome with bluish black macules over lips. (b) Tips of the fingers

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Navajo syndrome (poikiloderma with neutropenia)

It is an autosomal-recessive syndrome first described by Clericuzio in 1991 in 14 patients of Navajo descent.[18] Subsequently, it was seen to occur even in non-Navajo descent patients. Wang et al., therefore, proposed renaming this disorder “poikiloderma with neutropenia” (PN).[19] C16orf57 has recently been identified as a causative gene in PN.[20] It is characterized by poikiloderma, chronic neutropenia, recurrent sinopulmonary infections, bronchiectasis, and pachyonychia (thickened nails). Pigmentation is initially acral which then spreads to the trunk and is associated with recurrent pulmonary infections and pachyonychia.[18] Management includes the treatment and prevention of infections.

Dyschromatosis symmetrica hereditaria

This is the localized acral form of the autosomal-dominant disorder dyschromatosis, universalis hereditaria which has been mainly reported from Japan and India.[21],[22] It was originally believed to be the same as reticulate acropigmentation of Dohi but has recently been proven to be a genetically distinct entity with the defect localized to 12q21-q23 loci.[23] The onset is in early childhood with the mottled pigmentation starting from the hands and progressing to involve the trunk, extremities, and the face. The lesions are hyperpigmented macules admixed with hypopigmented lesions similar to those of acropigmentation of Dohi.[22] The lesions can infrequently also involve the palms, soles, and oral mucosa.[24] The nails may be hyperpigmented or dystrophic but the characteristic finding is pterygium formation. It may be associated with coxa valga, nerve compression, small stature, high-tone deafness, photosensitivity, and neurosensory hearing defect.[25]

Electron microscopy has shown this to be a disorder of melanosome production in epidermal melanin units rather than a disorder of melanocyte number.[26] For management, counseling is the best option as the condition is nonprogressive. Q-switched alexandrite laser may be helpful for the treatment of hyperpigmented lesions but they invariably recur.

Acromelanosis progressiva

The first case was reported by Furuya and Mishima in 1962. A few cases have been reported in literature but the inheritance of this disorder is still not definitely established.[27] It usually manifests as asymptomatic, brown to bluish-black skin pigmentation over the fingers and toes in newborns or during the first years of life. The pigmentation may later progress to involve the perianal area, genitalia, and even abdomen. Though the exact pathogenesis is unknown but it is hypothesized to be an epidermal hamartoma of melanocytes (epidermal melanocytosis). Histopathology shows an increased number of normal melanocytes in the basal epidermis.[27],[28] It may sometimes be associated with seizures or impaired intelligence quotient (IQ). There is usually no spontaneous regression of pigmentation. No active treatment is required.

Acquired diseases with only pigmentation

Laugier–Hunziker syndrome

This is an acquired, benign skin condition characterized by the hyperpigmented macules on the lips, buccal mucosa, and acral areas associated with the longitudinal melanonychia of nails.[29] It was first reported in 1970 by Laugier and Hunziker in five patients.[30] Though it seems to primarily affect the white population from European countries but sporadic cases from Asia including India have been reported in the last decade.[31] The etiology of this disorder is still unknown though no familial factor or systemic abnormality is associated with it. The pigmentation typically develops on the lower lip and buccal mucosa during early to middle adulthood. The tongue, gingiva, soft and hard palate, hands, and feet may also be involved.[29] The characteristic lesions are smooth-surfaced, brown/black/slate-colored 1–5 mm macules which may be lenticular, oval, or irregular in shape with well-defined or indistinct margins. These lesions may be single, multiple, or even confluent. The nails are affected in about 44–60% of the cases, with the finger nails usually being more frequently involved with one or two thick vertical longitudinal bands of pigmentation.[32],[33] The nail involvement has been classified by Baran into three types: (1) a single 1–2 mm wide longitudinal streak, (2) a double 2–3 mm wide longitudinal streaks, and (3) a homogeneous pigmentation of half of the nail.[33] Veraldi et al. added the fourth pattern of complete pigmentation of the nail.[32] The different types of nail involvement may be present simultaneously in one or more fingernails and/or toenails and the degree of nail pigmentation does not correspond to the different stages of the syndrome. Pseudo-Hutchinsons sign has also been reported.

On histopathology, there is increased basal layer pigmentation but a normal number of melanocytes with a normal morphology.[34] The accumulation of melanin is limited to the tips of epithelial rete pegs. These findings suggest that the condition is due to increased melanocytic activity rather than to an increased number of melanocytes. The treatment of the hyperpigmented lesions is usually performed by Q-switched Nd:YAG or Q-switched alexandrite laser or cryosurgery.[35] Sun protection is important to prevent reoccurrence.

Acquired diseases with pigmentation and systemic features

Cronkhite–Canada syndrome

This is a rare, noninherited condition with an estimated incidence of one per million.[36] It was first described by Cronkhite and Canada in 1955.[37] It can develop in all ethnic groups but the maximum cases have been reported from Japan. It is characterized by the cutaneous lesions of hyperpigmentation, onychodystrophy, and alopecia along with the systemic features of gastrointestinal hamartomatous polyposis, weight loss, and diarrhea.[38]

The onset of the disease occurs in fifth to sixth decade with diarrhea and dysgeusia as the most common initial symptoms. The dermatologic triad of alopecia, hyperpigmentation, and onychodystrophy occurs later.[39] The hyperpigmentation is maximum along the volar aspects of the fingers, but there is no mucosal pigmentation. Patients have diffuse polyposis of the gastrointestinal tract which is closely related to malabsorption which may lead to the ectodermal changes of cutaneous hyperpigmentation, dystrophic changes of the fingernails, and alopecia.

The exact etiology is not known but it is believed to be primarily autoimmune, because it has been associated with elevated antinuclear antibody and IgG4 levels.[36] Immunostaining for the IgG4 antibody is found to be significantly increased in Cronkhite Canada syndrome (CCS) polyps compared to other diseases and normal control tissues. It is also associated with various autoimmune diseases such as hypothyroidism, membranous glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis, and scleroderma.[36] Some infectious cause is also believed to play a role in the pathogenesis, because inflammatory cell infiltration with mononuclear cells and eosinophils is also present.[36],[40] The diagnosis is based on history, clinical examination, endoscopic findings of gastrointestinal polyposis, and histology. The histological specimens from stomach and small and large intestines show the typical features of benign juvenile-like or hamartomatous polyps, mild inflammatory cell infiltration, submucosal edema of the lamina propria, foveolar epithelium hyperplasia, focal hyperplasia, and cystic dilation of the mucosal glands.[41] The management of patients includes nutritional support, antibiotics, systemic glucocorticosteroids, anabolic steroids, histamine-receptor antagonists, and even surgical treatment.[42] Active screening should be performed for gastric and colonic cancers, because these are common complications (25% risk).[43]

Acral melanocytic lesions

Acral melanocytic lesions include both benign (congenital as well as acquired) melanocytic nevi and malignant conditions such as melanoma. The benign naevoid melanocytic lesions can usually be distinguished from the malignant ones by the ABCD criteria (asymmetry, irregular border, irregular color, diameter >6 mm). While acral cutaneous melanoma (CM) is uncommon, acral melanocytic nevi are relatively common. It is important to distinguish between the two, because benign lesions usually require no treatment other than reassurance while malignant lesions need to be treated aggressively.

Benign acral melanocytic nevus

Melanocytic nevi, broadly divided into congenital and acquired types, are common lesions which may also occur on the acral areas. The number of acral nevi appear to increase in rough proportion to the degree of skin pigmentation and also with ethnicity, age, and CM risk factors.[44] The color of the melanocytic nevi depends on the constitutive pigmentation and varies from light brown in whites to dark brown in blacks but are mostly tan to brown. The lesions are usually flat with only 3% being slightly raised. Acquired melanocytic nevi are typically less than a centimeter in diameter and evenly colored.

Markedly atypical-appearing acral melanocytic nevi are relatively uncommon in whites and blacks, but there is a notable higher rate of relatively large acral nevi in blacks than in whites, and a higher rate of relatively atypical features (dark brown or darker coloration and 3 or more shades or hues) in acral nevi of at least 5-mm diameter in blacks.[44] Congenital and acquired nevi may be differentiated on dermoscopy. The congenital lesions show more of globules, central blue grey pigmentation, and central enlarged pink ridges.[45] The clinical and histopathologic characteristics of nevi are required to distinguish them from melanoma. Management includes counseling and reassurance though some lesions may be surgically excised for cosmetic reasons.

Malignant: acral melanoma

Though the incidence of CM is significantly greater in whites than in blacks, the incidence of acral melanoma is similar.[46] Acral CM as a percentage of all CM cases has been reported to be 60–75% in blacks, 43–49% in Asians, and 5–7% in whites.[44]

The palms, soles, and subungual regions are the most predominant sites of malignant melanoma in Asians.[46] They present as variably shaped and colored melanocytic lesions which may be misdiagnosed as lentigines or melanocytic nevus leading to delay in correct diagnosis and treatment which is associated with a poorer outcome [Figure 4].[47] Standard criteria for the identification of early melanoma include overall asymmetry in the lesion along with an arrangement of proliferating melanocytes and their migration to the upper epidermis.[48] Atypical melanosis of the foot was described by Nogita et al. in 1994. It is a long standing lesion which is clinically suspicious for acral lentiginous melanoma in situ, but with subtle histopathologic findings.[49] Dermoscopy can be a very useful diagnostic tool for the differentiation of benign melanocytic lesions from early melanoma by the presence of irregular pigmentation and irregular dots/globules and vascular patterns.[46] Treatment is the surgical removal of the lesion with adequate margins or Mohs micrographic surgery.
Figure 4: Acral melanoma with positive Hutchinson sign

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Endocrine diseases

Endocrine diseases usually cause a diffuse hyperpigmentation which may be generalized or limited to certain areas.

Addison’s disease

It is a rare endocrinal disorder caused by insufficient production of cortisol and aldosterone by the adrenal glands. The pituitary gland tries to stimulate the adrenal glands by increasing the production of melanocyte-stimulating hormone and adrenocorticotropic hormone (ACTH) which leads to an increase in melanin production resulting in a “muddy” hyperpigmentation. Generalized diffuse hyperpigmentation of the skin is seen, which is classically described as “bronzing.” The hyperpigmentation is more prominent on the sun-exposed skin, pressure points (elbows and knees), and normally pigmented areas (creases, knuckles, perineum, axillae, areolae, palms, and soles). This hyperpigmentation is caused by the increased levels of beta-lipotropin or ACTH, each of which can stimulate melanocyte production.[50] The oral hyperpigmentation may be the first sign of Addison’s disease, because hyperpigmentation of the mucous membrane and skin usually precedes other symptoms by months to year.[51] Associated features include chronic worsening fatigue, loss of appetite, generalized weakness, weight loss, decreased pubic and axillary hair in women, hypotension, and abdominal pain.[50]

Patients with Addison’s disease are treated with replacement therapy with mineralocorticoids and glucocorticoids to reduce the drive for excess production of ACTH and melanocyte-stimulating hormone after performing ACTH stimulation test.[52]

Addisonian pigmentation

Addisonian pigmentation is a pigmentation which clinically resembles the pigmentation seen in Addison’s disease but may be due to various other reasons such as thyroid disorders or even vitamin B12 deficiency diseases [[Figure 5]a–[Figure 5]b].
Figure 5: (a) Addisonian pigmentation involving the dorsum of hands. (b) Palms.

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Thyroid disorders

Both hyperthyroidism and hypothyroidism cause a pattern of hyperpigmentation similar to that in Addison’s disease, especially in patients with darker complexions.[53] The subtle differences are less common involvement of the mucous membranes, nipples, and genital skin in hyperthyroidism and deposition of hemosiderin apart from basal melanosis, seen in Addison’s disease also.[54] Treatment is specific to the cause of hyperthyroidism/hypothyroidism and may involve antithyroid medications, surgical resection of the thyroid, or radioactive iodine therapy and alternatively thyroxine supplementation.[53]

Acral acanthosis nigricans

Acanthosis nigricans is characterized by the presence of a hyperpigmented, velvety cutaneous thickening that usually appears in flexural areas and is often associated with insulin resistance-mediated endocrine diseases.[55],[56] It may occur in other locations, such as the dorsum of the hands and feet. This “acral” type usually occurs in dark-skinned (African American descent), otherwise healthy individuals with lesions over the dorsal aspects of the hands and feet. A case of acral acanthosis nigricans secondary to the use of growth hormone has also been reported.[57]

Tripe palms, a paraneoplastic condition usually associated with malignant acanthosis nigricans, presents as rugose hyperkeratosis and prominent dermatoglyphics of the palms which has been likened to bovine gut lining. It is associated with underlying malignancy in 90% of the cases, with gastric cancer being the most common followed by lung cancer.[58]

Improvement occurs with the treatment of underlying condition, weight reduction, topical therapies such as etretinate, metformin, tretinoin, calcipotriol, urea, salicylic acid, CO2 laser ablation, and long pulsed alexandrite laser therapy.[59]

Metabolic diseases

Vitamin B12 deficiency

Vitamin B12 plays an important role in deoxyribonucleic acid (DNA) synthesis and its deficiency is associated with hematologic, neurologic, psychiatric, gastrointestinal, dermatologic, and cardiovascular manifestations.[60] Mucocutaneous changes occur less frequently than the hematologic, gastrointestinal, and nervous system manifestations. Nonvegetarian food is the main dietary source of vitamin B12 which is not synthesized in the human body. The common cause of vitamin B12 deficiency is malabsorption, usually due to pernicious anemia or gastric resection and rarely due to inadequate intake. It usually takes 2–5 years to develop even in the presence of severe malabsorption.[61] Megaloblastic pancytopenia due to cobalamin and folate deficiency usually occurs in the age group of 10–30 years with female preponderance. The predominant symptoms are fatigue, anorexia, gastritis, low grade fever, shortness of breath, palpitations, and mild jaundice.[60] Cutaneous manifestations are the skin hyperpigmentation, vitiligo, angular stomatitis, and hair changes including premature greying.[62] The characteristic hyperpigmentation is more commonly seen in darker-skinned patients over the dorsum of the hands and feet, with accentuation over terminal phalanges and interphalangeal joints along with oral mucosa pigmentation.[62],[63],[64] Linear streaks on the nails may also be seen. The pigmentation is due to an increase in the melanin synthesis rather than a defect in melanin.[64] The pigmentation is reversible over months with replacement therapy.[65] Management includes assessment for the cause of the deficiency and intramuscular cyanocobalamin injections.[60]

Pernicious anemia

It is an autoimmune condition characterized by a decrease in red blood cells occurring due to the decreased absorption of vitamin B12 from the intestines primarily because of a lack of intrinsic factor which is a special protein needed for its absorption. It is usually the underlying vitamin B12 deficiency which is responsible for the hyperpigmentation over the dorsum of the hands and feet and is completely reversed by its supplementation. The treatment of vitamin B12 deficiency in pernicious anemia is 1000 μg of vitamin B12 by intramuscular injection every day or every other day for 1–2 weeks, followed by monthly injections for 3 months, and thereafter every 3 months for life.[66]

Drug-induced pigmentation

Drug-induced pigmentation accounts for almost 10–20% of all cases of acquired hyperpigmentation. The pigmentation induced by drugs may occur as a result of various mechanisms depending on the causative medication [Table 2]. It may be due to the direct deposition of the drug or of special pigments synthesized under the influence of the drug or even of iron following damage to the dermal vessels. Alternatively, the drug may cause pigmentation by inducing melanin synthesis following various inflammatory cutaneous eruptions or photosensitivity.[67] In the hyperpigmentation due to photosensitivity or phototoxic reactions, the patients initially develop an erythematous allergic reaction followed by hyperpigmentation.[68] In some cases, the exact pathomechanism may be difficult to elucidate while in others more than one mechanism may be causing the pigmentation. Whatever may be the pathogenesis, the management requires the discontinuation of the causative drug.
Table 2: Drug induced

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Drug-induced pigmentation due to direct deposition

Clofazimine, minocycline, and antimalarial-induced hyperpigmentation are the common examples of this type of pigmentation which is time-dependant, that is, it increases with the duration of therapy.[69],[70] These patients usually present directly with a pigmentation in a diffuse pattern not associated with any preceding inflammatory reaction. The clofazimine-induced brown pigmentation is usually generalized but shows an accentuation in the sun-exposed areas and nails are commonly involved. Two types of pigments accumulate in the skin, namely, redox dye and lipofuscin-ceroid.[71] Drug-induced pigmentation usually occurs following long-term use over months and years and often resolves after the discontinuation of the causative drug.

Drug-induced pigmentation due to anticancer drugs

Hyperpigmentation, both diffuse and acral, is a common adverse effect of various anticancer drugs. Busulfan, cyclophosphamide, and hydroxyurea usually produce a diffuse hyperpigmentation while tegafur and capecitabine have been known to cause acral pigmentation.[72],[73],[74],[75] The acral pigmentation caused by anticancer drugs characteristically affects the pressure sites of the palms and soles. This predisposition is believed to be due to the increased blood flow to these areas leading to an increased drug deposition. The underlying pathogenesis of hyperpigmentation remains unknown but proposed mechanisms which induce melanin synthesis include: (a) direct stimulation of melanocytes, (b) deficiency of tyrosinase inhibitors, (c) formation of stable drug–melanin complexes.[67]

Hyperpigmentation is also a well-known adverse effect of intravenous therapy with 5-fluorouracil (an antiproliferative drug and precursor of capecitabine). This hyperpigmentation usually occurs on the photo-exposed skin by a photomediated pathogenetic mechanism.[76]

Fixed drug eruption

Various commonly used drugs such as barbiturates, ibuprofen, and sulfonamides commonly cause fixed drug eruption. It presents as recurrent plaque(s)/macules at fixed locations, commonly lips, genitalia, and acral areas subsequent to each exposure to the offending drug.[69] The lesions are usually nonitchy, sharply defined, erythema multiforme such as targetoid or circular macules which resolve spontaneously with postinflammatory hyperpigmentation. Histologically, the vacuolar type of interface pathology is associated with necrotic keratinocytes and lymphocytic infiltrate that obscures the dermo epidermal junction. Pigment incontinence is a prominent feature. Subepidermal vesiculation may be seen. Upper dermal inflammation consists of lymphohistiocytes, neutrophils, and eosinophils.[77] Treatment includes stopping the offending drug but the pigmentation takes a long time to lighten.

Drug-induced postinflammatory acral pigmentation

Postinflammatory acral pigmentation is usually a consequence of drug-induced erythema multiforme or the hand-foot syndrome. There is usually a history of preceding inflammatory lesions. The pigmentation is usually transient and resolves over time. The palms and soles are considered more sensitive to cytotoxic drugs due to the high proliferation rate of epidermal basal cells.

Hand-foot syndrome is a commonly reported adverse effect of various chemotherapy drugs such as capecitabine, sorafenib, and so on which has been classified into three grades. Grade I consists of minimal skin changes of erythema with swelling, but without pain or tenderness. Grade II is a progression of manifestations of Grade I with the pain and discomfort affecting daily activities of the patient. Grade III is the superimposition of blistering, moist desquamation, ulceration, and severe pain severely affecting the function.[78] Many authors consider acral hyperpigmentation to be an early presentation of HFS as the characteristic erythema may be masked in dark-skinned individuals (skin types IV–VI) and it may or may not progress to classical hand-foot syndrome (HFS).[79]

Iatrogenic − acral PUVA-induced pigmented macules

Chronic psorallen and ultraviolet A (PUVA) therapy is known to induce pigmented macules characterized by a lentiginous proliferation of large melanocytes which may be slightly atypical and are different from the sun-induced lentigines. A patient of chronic psoriasiform dermatitis of the palms and soles who received localized photochemotherapy (PUVA with the hand and foot units of UVA, ultraviolet A) has been reported to develop pigmented macular lesions over the treated areas. These lesions had varied histopathologic presentations including lentigines, atypical melanocytic proliferation, and a junctional nevus suggesting a wide clinic-pathologic spectrum in the PUVA-induced pigmented macules.[80]

Heavy metal induced

Though “heavy metals” are defined as the elements with a specific gravity >5.0 but the term is also broadly used for the metals and even semimetals which have a potential for toxicity. The exposure to these metals may occur through diet, medications, occupation, and even from environment. Certain metals such as aluminum, bismuth, gold, gallium, lithium, and silver are sometimes used for medical purposes. The metal-induced pigmentation is partly due to deposition of metal particles and partly due to an increase in melanin production. In chrysiasis, the ultraviolet light may induce preferential gold deposition in the dermis which further stimulates the melanin production. Gold, silver, mercury, and bismuth typically produce a slate blue pigmentation of the exposed skin and mucosae. Systemic arsenic ingestion results in a generalized distribution of hyperpigmented lesions in a raindrop pattern over the body including the palms and soles. Management includes avoidance of exposure to the metal as well as protection from sun exposure.[69],[81]

Argyria

Argyria results from the deposition of silver in the skin subsequent to prolonged ingestion of silver. It is an exotic cause of hyperpigmentation. In India, the exposure is mainly through ingestion of silver coated sweets (mithai with silver virq) and silver coated cardamom, betel nut, and fennel seeds (consumed as mouth fresheners for years). Argyria produces distinctive gray‑blue discoloration in a photo-distributed pattern.[82] Similar discoloration can also be seen over ear cartilage, in the nails, mucous membranes, and sclera. Localized cutaneous argyria due to prolonged contact with silver salts or silver jewellery or from the penetration of acupuncture needles is also reported. Such lesions may mimic melanocytic lesions including melanoma.

Autoimmune − lichen planus

It is a pruritic, benign, papulosquamous, inflammatory dermatosis of unknown etiology that affects the skin, mucus membranes, hair, and nails. Classically, it presents with violaceous, scaly, flat-topped, polygonal papules over the flexures rarely involving the palms and soles. Palmoplantar lichen planus (LP) usually presents with yellowish hyperkeratotic plaques with or without itching but it may present as violaceous macular or papular lesions [Figure 6].[83] LP pigmentosus usually causes diffuse or discrete macular violaceous pigmentation over the sun-exposed areas, that is, the face and arms. Histopathology usually confirms the diagnosis. Various treatment modalities for palmoplantar LP include topical steroids, keratolytic agents such as salicylic acid, topical tazarotene and systemic steroid, acitretin, cyclosporine, and so on.[84]
Figure 6: A patient of lichen planus with postinflammatory macules on the plantar surface of the foot extending over ankle joint

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Infection − secondary syphilis

Syphilis is a sexually transmitted disease caused by Treponema pallidum. Secondary syphilitic lesions are characterized commonly by a generalized papular, plaque, or nodular eruption with characteristic involvement of the palms and soles [Figure 7]. Buschke Ollendorf sign is positive, that is, rebound deep dermal tenderness is depicted on pressing with the pin head over the lesions. Secondary syphilis is typically a systemic disease, with the patient presenting with a variety of symptoms, such as malaise, sore throat, headache, weight loss, low-grade fever, and muscle aches, in addition to the dermatologic manifestations including lesions over the palms and soles. Lymph node enlargement is present in the great majority of patients. Diagnosis is based on Venereal Disease Research Laboratory test (VDRL) test positivity in a titer >1:8 and confirmed by  Treponema pallidum Scientific Name Search emagglutination assay (TPHA) test. Treatment involves benzathine penicillin injections.[85]
Figure 7: A patient of secondary syphilis with dusky erythematous maculopapular lesions on the soles

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  Exogenous pigmentation Top


The exogenous pigmentation usually over the palms and soles may be due to various chemicals applied such as henna, alta, hair dye, and so on or even due to certain insects. There may be diffuse or bizarre-shaped pigmentation with or without inflammatory changes. A detailed history and clinical suspicion is essential to make a diagnosis. The hyperpigmentation tends to improve with time and sometimes rubbing the affected site with alcohol or ether may dissolve the pigment.

Insect induced

Certain insects such as millipedes, blister beetles, and so on are known to release chemicals that can cause erythema and hyperpigmentation. The fluid released by these insects when threatened usually contains benzoquinone but depending on the order of Diplopoda may also contain quinazolinones or hydrogen cyanide. Contact with this fluid can cause inflammatory reactions and various forms of pigmentation or discoloration (black, brown, red, or purple) [Figure 8]. A case of dark macular pigmentation on the sole of the foot following stepping on a millipede (“gongolos”) has been reported which on dermatoscopy showed a parallel ridge pattern thought to be typical for acral melanoma.[86] It is essential to keep in mind that the parallel ridge pattern may also be seen in exogenous pigmentation, racial melanosis, lentiginous conditions, etc. and is not exclusive to melanoma.
Figure 8: Insect-induced brownish macules on the sole of a child

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Nicotine staining in smokers

There is usually a yellow to brown pigmentation over the surfaces of the fingers in contact with the cigarette known as “smoker’s fingers.”[87] It tends to disappear once the person gives up smoking.

Thus, there are various causes of acral pigmentation varying from genetic to acquired, benign to malignant, autoimmune to infectious, drug induced, nutritional deficiencies, postinflammatory, and even exogenous reasons. The pigmentation may be occurring in isolation or associated with various systemic features. A careful history and detailed examination of the patients usually helps in delineating the underlying pathogenetic mechanisms [Table 3]. An earlier age of onset of pigmentation, a positive family history, and a reticulate or mottled pattern usually point to a genetic cause. The diffuse pattern of pigmentation is usually seen in racial, endocrine diseases, and nutritional deficiencies. Postinflammatory acral pigmentation may follow both infectious and autoimmune diseases [Figure 9] and may even be drug induced. A correct diagnosis is important to decide on the management which varies from reassurance and counseling to active treatment.
Table 3: Approach to a patient of acral melanosis

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Figure 9: A patient of systemic lupus erythematosus with postinflammatory pigmentation over the palms

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Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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